Hepatocellular carcinoma (HCC) is the third most common cause of cancer death worldwide. HCC is among the fastest growing group of cancer deaths in the U.S mainly because of the increasing rate of hepatitis C viral (HCV)- infections. There exists an obvious need for biomarkers that could predict those hepatitis positive individuals who develop HCC at early stages when definitive therapy is potentially curative. Circulating microRNAs (miRNAs) hold great potential as cancer biomarkers. There are no published studies that have identified a serum or plasma miRNA signature in HCV infected patients that go on to develop HCC. This research aims to develop a circulating miRNA signature to be used as biomarkers for HCV-associated HCC. Specific Aim 1: The goal of Aim 1 is to identify and validate a miRNA signature for HCC in HCV-infected individuals. As the training set, we will profile miRNAs in a cohort of plasma samples from HCV positive individuals, half of which are HCC+ (Mayo cohort). The most informative miRNAs will then be validated in a testing set of plasma samples. Specific Aim 2: The panel of miRNAs identified in Aim 1 will be validated in a second cohort of 100 serum samples (EDRN cohort). Approximately 60% of the EDRN reference set is HCV positive. Should the miRNA signature perform equal to or better than that of serum alpha fetoprotein, we will be granted access to a larger EDRN validation set of 750 serum samples. Successful completion of this research will lead to prospective collection and evaluation of the miRNA signature in HCV-infected individuals prior to the development of HCC. PUBLIC HEALTH RELEVANCE: Liver cancers, of which over 75% is hepatocellular carcinoma (HCC), are the fastest growing cause of cancer death in the United States and are already the third most common cause of cancer death worldwide. The cause for the increased incidence in the United States is thought to be largely from the increased Hepatitis-C virus (HCV) infection rate throughout the population. There is a lack of an efficent, inexpensive test to monitor HCV+ individuals for the development of HCC. Biomarkers are one avenue to monitor these patients. One of the most recent molecules to be studied as biomarkers are microRNA (miRNA) in the tissues and body fluids including the blood. This study will see to indentify how the miRNA pattern changes in the blood of HCV+ individuals when they develop HCC so that the disease may be found early and they can see curative treatment.